To further explore the potential for cognitive enhancement utilizing nicotinic stimulation in Alzheimer's disease (AD), 6 otherwise healthy subjects with moderate AD received placebo and 3 doses (6, 12, and 23 mg) of the novel selective cholinergic channel activator (nicotinic agonist) ABT-418 over 6 hours in a double-blind, within-subjects, repeated-measures design. Subjects showed significant improvements in verbal learning and memory as reflected by improved total recall and a decline in recall failure. Similar, though not as robust improvements were seen in nonverbal learning tasks such as spatial learning and memory, and repeated acquisition. Effects on reaction time were modest. No significant behavioral, vital sign, or physical side effects were seen. These data represent perhaps the strongest evidence to date that stimulation of nicotinic receptors can improve the acquisition and retention of verbal information (declarative memory) in humans. Previously, it has been difficult to demonstrate with nicotine itself that stimulation of nicotinic receptors produces true learning or memory improvement effects and most of the cognitive effects of nicotine have been interpreted as due to attentional effects. However, nicotine's effects are most often seen in tasks that have a large attentional load and the verbal learning tasks that improved after acute administration of ABT-418 in this study required focused attention and significant cognitive effort. Further studies are required to determine if selective nicotinic stimulation by subtype-specific agonists will help determine whether nicotinic stimulation assists at maintaining or focusing attention, improves encoding, augments retrieval (from working memory), or more likely, affects a combination of processes. It is not possible from this study to assess whether the cognitive improvements seen here will translate in to clinically manifest benefits. Nonetheless, the possible combination of cognitive enhancement with mild anxiolytic effects is an attractive one, and longer-term studies with this agent or similar subtype-selective agonists are warranted. These results confirm that stimulating central nicotinic receptors has acute cognitive benefit in AD patients. These findings suggest that selective nicotinic agonists have a larger therapeutic index than nicotine, and further studies with this or similar agents in AD and/or Parkinson's disease are warranted. This protocol is currently closed.